Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment
Keven M. Robinson, Krishnaveni Ramanan, Joshua M. Tobin, Kara L. Nickolich, Matthew J. Pilewski, Nicole L. Kallewaard, Bret R. Sellman, Taylor S. Cohen, John F. Alcorn
Keven M. Robinson, Krishnaveni Ramanan, Joshua M. Tobin, Kara L. Nickolich, Matthew J. Pilewski, Nicole L. Kallewaard, Bret R. Sellman, Taylor S. Cohen, John F. Alcorn
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Research Article Immunology Infectious disease

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment

Abstract

Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti–Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.

Authors

Keven M. Robinson, Krishnaveni Ramanan, Joshua M. Tobin, Kara L. Nickolich, Matthew J. Pilewski, Nicole L. Kallewaard, Bret R. Sellman, Taylor S. Cohen, John F. Alcorn

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Figure 1

Influenza HA targeting mAb FY1 decreases acute lung injury and protects against influenza-associated bacterial pneumonia.

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Influenza HA targeting mAb FY1 decreases acute lung injury and protects ...
(A) Study design with groups of C57BL/6 mice infected with 100 PFUs of influenza A PR/8/34 and receiving a single dose of FY1 or IgG control on days 1 to 5 after influenza infection. Mice received secondary infection with 5 × 107 CFUs of MRSA on day 6 after influenza, and samples were harvested 24 hours following bacterial infection (n = 8). (B) Bacterial colony counts in the lung. (C and D) Weight loss on days 6 and 7 after influenza infection. (E) Survival curves of mice that received FY1 or IgG control on days 1, 3, or 5 after influenza infection. Mice received secondary infection with 5 × 108 CFUs of MRSA on day 6 after influenza (n = 12). (F and G) Total protein and IgM concentrations in the BALF. *P < 0.05. Significance was tested by 1-way ANOVA using Dunnett’s multiple comparison test except for E where a log-rank Mantel-Cox test was performed. Each experiment was independently performed twice, and data are shown from combined experiments. Data represent mean ± SEM.